Systematic review of international studies evaluating MDRD and CKD-EPI estimated glomerular filtration rate (eGFR) equations in Black adults

Use of race adjustment in estimating glomerular filtration rate (eGFR) has been challenged given concerns that it may negatively impact the clinical care of Black patients, as it results in Black patients being systematically assigned higher eGFR values than non-Black patients. We conducted a systematic review to assess how well eGFR, with and without race adjustment, estimates measured GFR (mGFR) in Black adults globally. A search across multiple databases for articles published from 1999 to May 2021 that compared eGFR to mGFR and reported outcomes by Black race was performed. We included studies that assessed eGFR using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICr) creatinine equations. Risk of study bias and applicability were assessed with the QUality Assessment of Diagnostic Accuracy Studies-2. Of 13,167 citations identified, 12 met the data synthesis criteria (unique patient cohorts in which eGFR was compared to mGFR with and without race adjustment). The studies included patients with and without kidney disease from Africa (n = 6), the United States (n = 3), Europe (n = 2), and Brazil (n = 1). Of 11 CKD-EPI equation studies, all assessed bias, 8 assessed accuracy, 6 assessed precision, and 5 assessed correlation/concordance. Of 7 MDRD equation studies, all assessed bias, 6 assessed accuracy, 5 assessed precision, and 3 assessed correlation/concordance. The majority of studies found that removal of race adjustment improved bias, accuracy, and precision of eGFR equations for Black adults. Risk of study bias was often unclear, but applicability concerns were low. Our systematic review supports the need for future studies to be conducted in diverse populations to assess the possibility of alternative approaches for estimating GFR. This study additionally provides systematic-level evidence for the American Society of Nephrology—National Kidney Foundation Task Force efforts to pursue other options for GFR estimation.

Introduction Accurate assessment of kidney function is essential for proper diagnosis, staging, and management of chronic kidney disease (CKD). The gold standard for evaluating kidney function is measured glomerular filtration rate (mGFR), which relies on infusing chemicals, such as iothalamate, into the blood and quantifying urine clearance. Estimated GFR (eGFR) is based on the measurement of serum filtration markers, such as creatinine or cystatin C, and therefore is more practical to obtain in clinical practice [1].
The Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are commonly used in the United States (U.S.) and internationally. Each includes serum creatinine measurement as a key variable for determining eGFR [2][3][4]. The equations were developed in large U.S. cohorts and include race, sex, and age variables [5]. Use of the race variable increases reported eGFR by 21.2% (MDRD) or 15.9% (CKD-EPI) in Black patients [3,6].
While sex and age are biological variables, the meaning and classification of race have evolved over time. Definitions of race are often inconsistently applied, and the utility of race adjustment in non-U.S. populations is unclear [7]. The appropriateness of including race in clinical algorithms has been questioned given that race is a sociopolitical rather than biological construct and the urgent need for clinical medicine to confront structural racism in our practices [7][8][9][10][11][12][13][14].
In the U.S., the prevalence of chronic kidney disease (CKD) and end-stage renal disease is higher among Black Americans relative to White Americans [15,16]. While genetic and social factors play a large role in kidney health disparities in the U.S., inappropriately including race in eGFR equations can increase health inequities [14,17]. Race-adjusted glomerular filtration rate (GFR) estimates could delay clinical care dependent on eGFR thresholds, such as specialist referrals or transplantation, and impact dosing decisions [8,9,14].
Concerns about health equity and the lack of evidence for race adjustment led several institutions to omit race from eGFR equations [18]. Some researchers cautioned about unintended consequences, including the potential for Black patients to be overdiagnosed and overtreated, or prematurely deprescribed medications such as metformin or empagliflozin [8,11,14,18]. In July 2020, the National Kidney Foundation and the American Society of Nephrology (NKF-ASN) created a task force to evaluate the inclusion of race in eGFR equations in response to growing controversy [19]. The task force ultimately recommended a new 2021 CKD-EPI creatinine equation refit without the race variable for U.S. adults [20,21].
A systematic review of the global literature on the use of eGFR equations for Black patients is needed to inform clinical decision-making worldwide [14] and strengthen the adoption of the NKF-ASN task force recommendations. Our team conducted a systematic review to provide the highest level of evidence for assessing the use of eGFR race adjustment in Black patients. We aimed to answer the question: How well does eGFR, with and without race adjustment, predict mGFR in Black adults in the U.S. and internationally?

Protocol
A protocol with investigation parameters, data extraction procedures, and quality assessment processes was used to guide the review process (S1 Table). The protocol and systematic review are reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (S2 Table) [22][23][24].

Eligibility criteria
Inclusion criteria were validation and/or comparison studies that included Black adults (ages 18 and older), compared an eGFR formula to mGFR or to another eGFR formula, and were published in English, French, Spanish, or Portuguese. All research article types were eligible, including conference abstracts. Items were excluded if they did not use mGFR as a reference test as assessed by 51 Cr-EDTA, inulin, 125 I-iothalamate, iohexol, or 99m Tc-DTPA exogenous markers, did not use either an MDRD or CKD-EPI eGFR formula as an index test, did not use isotope dilution mass spectrometry (IDMS) traceable creatinine assays, or did not report outcomes by Black race. Conference abstracts published prior to 2015 were excluded as the findings would likely have been later published as journal articles. Studies reporting preliminary results were excluded when a more complete publication with the final results was identified.

Search process
PubMed, Embase (via OVID), ScienceDirect (Elsevier), Web of Science, and Google Scholar (via the Publish or Perish software [25]) were searched for citations published after January 1, 1999. Database searches, originally conducted on October 23, 2020, were re-executed on May 6, 2021. All search results were deduplicated based on unique identifiers (e.g., digital object identifier, article title). See S1 File for the full search strategies and search process details.

Study screening and data extraction
The abstracts and full-text of each publication were independently screened by 2 reviewers. Decisions were collected via REDCap1 [26] forms created by the study team. Discordant ratings between reviewers were resolved using an independent third person. Data extraction was also conducted independently by 2 reviewers for each included study meeting eligibility criteria; a third person adjudicated non-consensus ratings. Data extracted included: citation details, country of study, study aims, total participants, population characteristics (e.g., demographics, kidney disease status), study eligibility criteria, eGFR and mGFR calculation methods, type of eGFR equation used, eGFR as assessed with and/or without race coefficient in Black adults, mGFR in Black adults, performance measure results, and statistical significance.
The main outcomes included bias (defined as the difference between eGFR and mGFR), accuracy (proportion of patients with eGFR values within a given threshold, such as 30% of mGFR, also referred to as P 30 ), precision, and correlation/concordance of eGFR and mGFR. Additional outcomes were reporting of social determinants of health (e.g., income, educational level, lifestyle choices) and non-GFR determinants of creatinine: underlying co-morbidities (e.g., liver disease, anorexia, chronic illnesses), and medication use that can lead to false elevation of creatinine or interfere with creatinine measurement assays (e.g., antibiotics, chemotherapeutic agents).

Quality assessment
Applicability and risk of study bias were assessed independently by 2 reviewers using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS-2) [27]. The instrument includes "signaling" questions to assess bias in 4 domains (patient selection, index test, reference standard, and flow and timing) and questions in 3 domains (patient selection, index test, and reference standard) to assess the applicability of each study to the overall systematic review question.
In the patient selection domain, we assessed the appropriateness of the exclusion criteria relative to the aims of the specific study and against a pre-defined list of non-GFR determinants of creatinine; if exclusions were explained by these factors, we marked "yes" for the signaling question of whether the study avoided inappropriate exclusions. For pooled data studies, if it was unclear how the authors arrived at the number of participants compared with the original studies, we used a response of "unclear" for the exclusion criteria question. Concern that the included patients did not match the review question was rated as "high" if there was uncertainty that the study did not include only Black adults (e.g., participants <18 years old or of "mixed ancestry"). The index tests were defined as either the MDRD or CKD-EPI and the reference standard was mGFR using any of the following exogenous markers: 51 Cr-EDTA, inulin, 125 I-iothalamate, iohexol, or 99m Tc-DTPA. In the flow and timing domain, an appropriate interval between the index and reference tests was defined as eGFR and mGFR samples drawn within 24 hours of each other.
If all responses to the signaling questions were "yes," we assigned a rating of "low" to the domain; if all responses were "no," we assigned a rating of "high." For any combination of responses (i.e., any combination of "yes," "no," and/or "unclear"), we assigned a rating of "unclear." Discordant ratings between reviewers were resolved through discussion.
Data synthesis. Studies were grouped by the methods used to assess eGFR vs. mGFR performance. Three categories of publications were identified: studies that evaluated eGFR equations 1) with and without race adjustment, 2) with race adjustment, and 3) without race adjustment. Data synthesis was conducted only on studies that assessed eGFR equations both with and without race adjustment compared to mGFR (category 1) in order to have directly comparable eGFR performance data for the review analysis. Additionally, when multiple publications reporting outcomes data on the same patient population were identified, the publication with the most complete data set was retained for analysis. Data are presented using descriptive tables. The outcomes of bias, accuracy, precision, and agreement measures (e.g., correlations and concordance), are summarized by eGFR equation. No minimum number of studies was needed to report results.

Results
In all, 24,850 results were retrieved (Fig 1) from database searches. Fifteen additional articles were identified through handsearching of 256 articles flagged for reference checking during the screening process. After removing duplicate records and pre-2015 conference abstracts, the titles and abstracts of 13,167 citations were screened. Of these, 11,919 were excluded after abstract review, and 1,190 were excluded at full-text review. Thirty-four articles met all eligibility criteria, of which, 12 met data synthesis criteria as described above.

Study characteristics
Twelve studies evaluating eGFR equations both with and without race adjustment vs. mGFR were included in the data synthesis (Table 1). See S3 Table for the study characteristics of the remaining 22 studies identified in the review.
The geographic distribution of the studies varied. Three studies (25.0%) evaluated eGFR in the U.S. [10,34,37]. The U.S. studies included a retrospective validation study of HIV-positive and -negative individuals, which evaluated the bias and P 30 of the CKD-EPI Cr equation [33], a cross-sectional validation study of patients with and without CKD, which evaluated the bias and root mean square error (RMSE) of the CKD-EPI Cr equation [10], and a prospective cohort study using data from the Chronic Renal Insufficiency Cohort (CRIC) study, which evaluated the bias of CKD-EPI Cr [37]. Six studies (50.0%) evaluated eGFR in African countries: South Africa [29,31,36,38], the Ivory Coast [28], the Democratic Republic of the Congo [28], and Kenya [32]. One study (8.3%) was conducted in France [35], 1 study (8.3%) in the United Kingdom (UK) [33], and 1 (8.3%) was conducted in Brazil [30]. Table 2 presents the bias, accuracy, and precision performance results of the eGFR equations.

Bias
Of the 11 studies evaluating bias of CKD-EPI Cr equations, with and without race adjustment, bias improved with removal of race adjustment in 10 studies ( including 2 U.S. studies [13,37]. By contrast, a U.S. study of patients with and without CKD that used the original data set from which the CKD-EPI Cr equation was derived found that bias worsened with removal of race adjustment [10]. In all 7 studies evaluating bias of the 4-variable MDRD equation with and without race adjustment, bias improved with race adjustment removal [28, 31-34, 36, 38].
In all 6 studies assessing the accuracy of MDRD equations with and without race adjustment, removal of the race coefficient improved accuracy (Table 2) [28, 31-33, 36, 38]. Across all studies reporting accuracy outcomes, irrespective of eGFR equation evaluated, all used P 30 as an accuracy measure. Additional accuracy thresholds reported included P 20 [38], P 15 [31], and P 10 [29,32].

Precision
Precision improved with removal of race adjustment in 4 of 6 studies evaluating the precision of CKD-EPI Cr , with and without race adjustment (Table 2) [28,31,33,38]. Precision was evaluated via different methodologies, including RMSE-calculated as the square root of the mean squared differences of eGFR and mGFR, the interquartile interval (IQR) of the difference between eGFR and mGFR, standard deviation of bias, or the interquartile range of the eGFR and mGFR differences. In 2 studies, including a U.S. study [10] and a study in a Brazilian population [30], precision worsened with the removal of race adjustment.
Five studies evaluated precision of the 4-variable MDRD equation (Table 2) and reported improvement when race adjustment was removed [28,31,33,36,38]. Precision was measured as standard deviation of bias or the interquartile range of the eGFR and mGFR differences. Participants were described as originating from Sub-Saharan Africa and the French West Indies, though not explicitly described as "black" by the authors. b Study reports "n" as "observations," not individual patients.

Correlation and concordance
Overall, the findings were mixed in the 6 studies reporting correlation between CKD-EPI Cr equations, with and without race adjustment, and mGFR (S4 Table) [28-30, 32, 35, 38]. Arlet and colleagues (2012) found that the difference between eGFR and mGFR decreased with increasing GFR values for CKD-EPI Cr with race adjustment (r = -0.23, p = 0.06) and without race adjustment (r = -0.43, p<0.001) [35]. Bukabau et al. report increased correlation between eGFR and mGFR in a large cohort of participants from the Democratic Republic of Congo and the Ivory Coast with removal of the race coefficient compared to inclusion of the race coefficient (Lin's Concordance Correlation Coefficient of 0.81 vs. 0.71 respectively) [28]. Rocha and colleagues found that concordance was 52.5% for African Brazilians using CKD-EPI Cr with race adjustment, and 54.1% without race adjustment [30]. Moodley and colleagues [29] observed a high correlation both with and without race adjustment (R 2 = 0.83 for females; R 2 = 0.86 for males). Holness (2020) reports agreement between CKD-EPI Cr and mGFR; with race adjustment, the 95% limits of agreement were -14.5-55.2 and without race adjustment, -17.9-35.7 [38]. However, correlation was poor in a study by Wyatt and colleagues (R 2 = 0.23 both with and without race adjustment) [32]. In 3 studies assessing the correlation between MDRD and mGFR (S4 Table), two reported increased correlation with removal of eGFR race adjustment [28,35]. However, Wyatt and colleagues report no difference in correlation or variance inflation when the race variable is removed from the eGFR equation [32].

Social determinants of health and non-creatinine determinants of GFR
Only 2 studies reported social determinants of health and neither provided eGFR vs. mGFR performance outcomes (i.e., bias, accuracy, precision) by social determinants of health [34,  Bias differences were calculated as eGFR-mGFR (units in ml/min per 1.73 m 2 ); Percentage bias was calculated by study authors as (eGFR-mGFR)/eGFR. b SD of the bias c IQR of the difference between eGFR and mGFR d RMSE of eGFR vs. mGFR regression e RMSE = "square root of the mean of squared differences between mGFR and eGFR" f Precision = "median and interquartile interval of the difference between estimated GFR and measured GFR" g Authors calculated RMSE for both accuracy and precision h Interquartile range for the difference between estimated and measured GFR i This value is reported as 48.3% in the narrative results and 43.3% in Table 2

PLOS ONE
Systematic review: Race adjustment in eGFR equations 37]. Smoking status was reported in both studies, with Atta at al. also describing the income, education level, and insurance status of their study population (Black patients with mild to moderate CKD) [34]. Non-GFR determinants of creatinine were reported at baseline in 4 studies [32,34,35,38]; however, none reported eGFR vs. mGFR performance by non-GFR determinants of creatinine.

Quality assessment outcomes
Three studies analyzed for the review had low risk of bias for the patient selection domain (Table 3). Nine studies had unclear risk of bias for patient selection (Table 3), including 3 retrospective studies [29,33,34] and 1 study evaluating outcomes based on multiple measurements for some patients [34]. All 12 studies analyzed for the review were rated as having unclear risk of bias for the index test and reference standard domains due to a lack of information about whether the tests were interpreted without knowledge of each other. Regarding flow and timing, 6 studies had low risk of bias [28-30, 34, 36, 38], and the remaining had unclear bias. Applicability concerns were low for most studies and domains, except for patient selection in 1 study [38]. See S5 Table for quality assessment ratings of the 22 studies not included in the narrative synthesis.

Discussion
Previous efforts revealed the need for a comprehensive, systematic review of international scope to inform the use of eGFR estimation in Black patients [40], and our study is among the first systematic reviews to assess worldwide evidence related to adjustment for Black race in eGFR equations. The most commonly reported performance metrics identified from our systematic review were bias, precision, and accuracy, which improved in the majority of studies when race was removed from eGFR equations. Concordance and correlation were less often evaluated and seldom assessed in a standardized way, making it difficult to draw conclusions. Results from the QUADAS-2 quality assessment indicated that while there was low concern regarding the applicability of the included studies for the overall systematic review question, risk of study bias was difficult to assess due to inadequate reporting and variations in study methodology and design.
Recently, new recommendations have been put forth by NKF-ASN and the National Institute for Health and Care Excellence (NICE) to remove race adjustment from eGFR equations [20,21,41,42]. The NKF-ASN task force recommended a new CKD-EPI Cr equation refit without a race adjustment for U.S. adults [20,21]. We did not include the study reporting the new CKD-EPI Cr equation [21] in our systematic review, since it was published outside of our preestablished date parameters. While the NKF-ASN task force recommended use of the new CKD-EPI Cr equation refit without race, they noted that accuracy may improve with use of equations combining filtration markers. Inker and colleagues (2021) found that use of a new CKD-EPI equation incorporating both creatinine and cystatin C, without race adjustment (new CKD-EPI Cr-Cys ), was more accurate than the new CKD-EPI Cr equation, which underestimated mGFR in Black adults and overestimated mGFR in non-Black adults in the U.S. [21]. Future validation studies are needed to assess the performance of the new CKD-EPI equations in other countries and across a variety of clinical settings.
Our study has several limitations. We only included studies that compared the performance of eGFR equations both with and without race adjustment. We did not evaluate differences in performance between the multiple versions of the CKD-EPI and MDRD equations, thought less clinically relevant especially given recent guidelines. Measured GFR was not assessed consistently between studies. Many of the included studies did not assess the statistical significance  of outcome measures when race adjustment was removed. None of the included studies assessed the impact of social determinants of health and non-creatinine determinants of GFR. Many studies did not report how race was determined; since race is inconsistently defined across populations [43], this contributes to heterogeneity in the findings. Risk of overall study bias was unclear for many studies due to inadequate reporting and variations in study methodology. A further limitation is the potential risk of publication bias; however, we minimized this risk by conducting a comprehensive literature review that spanned across multiple databases and included grey literature sources.
Our study focused on Black participants rather than mixed populations. While we recognize the value in studies with mixed populations, we chose to focus on studies with Black participants in order to optimally assess the study's main objective of determining how well eGFR with and without race adjustment estimates mGFR in Black adults across the world. Given the paucity of data on eGFR in Black people in the U.S., and the historical limited participation of Black people in clinical trials including kidney-focused trials [44], the focus of this review on Black participants is an added strength of our study.
Limitations in eGFR due to variation in non-GFR determinants of serum creatinine could be relevant in our systematic review, which included studies with heterogenous populations. In studies of sicker patient populations, eGFR Cr likely overestimates kidney function, and removal of the race coefficient can bring kidney function closer to the expected value. However, such findings are coincidental and do not provide additional evidence to support that eGFR equations without the race coefficient outperform eGFR equations with the race coefficient. The sub-optimal accuracy measures observed in many of the studies included in our systematic review support the need for continued efforts to improve the accuracy of eGFR within and outside the U.S. More modern and elaborate approaches are gradually replacing existing simplistic methods used in MDRD and CKD-EPI equations. Examples include Q-values in the new EKFC-equation [45] and creatinine growth curves [46]. Widespread use of these elaborate methods is currently limited by a paucity of external validation studies.
This novel, in-depth and worldwide systematic review, provides the highest level of evidence against race adjustment when estimating GFR [20,21,41,42]. Race is an inappropriate proxy for genetics all over the world, and efforts to eliminate its use in estimating GFR should be global. In addition to tracking the performance of the newly recommended race-free eGFR equations, future research should prioritize health equity [47,48] by assessing the impact of social determinants of racial disparities in kidney disease on GFR estimates and ensuring enrollment of diverse participants across the world in validation trials of GFR equations [47,48].